APPLICANT'S ABSTRACT: In our previous grant award period, we conducted a randomized double-blind placebo-controlled clinical trial in alcoholics (N=321) who received 12-weeks of standardized Cognitive Behavioral Therapy (CBT) which showed that the 5-HT3 antagonist, ondansetron (1 - 16 mcg/kg b.i.d.) was superior to placebo at improving self-report and objective measures of drinking in Early Onset Alcoholics (EOA) but not Late Onset Alcoholics (LOA). We postulate that ondansetron's differential effectiveness among EOA was due to their greater disposition to genetically-determined 5HT dysfunction. We now propose to determine if alcoholics who differ on genetically controlled variations on activity at the serotonin transporter (SERT) respond differently to ondansetron treatment. SERT contains the only known functional polymorphism of the 5-HT system, and is therefore an excellent candidate to target. The LL variant the of 5'-flanking regulatory region (5'-HTTLPR) of SERT differs from the SS/SL forms in having about two times greater 5-HT uptake into the pre-synaptic neuron, and is therefore associated with reduced intrasynaptic 5-HT levels. While chronic alcoholism appears to be differentially toxic to SERT in the LL variant, the resultant effect remains that of reduced transynaptic 5-HT neurotransmission which can upregulate post-synaptic 5-HT3 receptors. We hypothesize that ondansetron's treatment effectiveness may be related to blockade of these upregulated receptors. We therefore plan to test the predictions from our hypotheses that: a) alcoholics with the LL variant, compared to those with the SS/SL forms, will respond better to ondansetron, and b) that the LL variant will account for additional variance in ondansetron treatment response over and above that of age of onset. SPECT imaging with 123I-b-CIT binding will be used to test whether the interaction between genotypic differences of SERT and drinking behavior, affect phenotypic expression of SERT density in the raphe nuclei. We will recruit currently drinking alcoholics until we identify and enroll 160 with the LL variant and 160 with the SS/SL form of SERT; 80 each EOA and 80 each LOA. Subjects in each of these four groups will receive one week of single-blind placebo lead-in followed by randomization to 11 weeks of double-blind treatment with ondansetron (4 mcg/kg b.i.d.) or placebo. Randomization will be matched for ethnicity and baseline drinking levels. All patients will receive weekly standardized group CBT. SPECT scans with 123I- b-CIT will be conducted at intake and study end. This study applies state of the art pharmacogenetic and neuroimaging techniques to systematically extend our previous work investigating serotonergic mechanisms in alcoholism treatment. Also, we aim to clarify the complex relationship between 5'-HTTLPR genotype, SERT phenotype, age of alcoholism onset, and ondansetron treatment responsiveness.